In recent years a series of highly active analogues of the natural releasing hormone LH-RH have been prepared. These compounds are referred to as super agonists and exhibit so called "paradoxical" high dose effects, for example, blockage of ovulation in the female, suppression of spermatogenesis in the male, and suppression of normal circulating levels of sexual steroids of gonadal origin, including reduction in accessory organ weight in the male and female. In general these compounds can be used for contraception in the male and female, for reduction of accessory organ weight (e.g. prostate size in the male) and so forth.
The natural LH-RH has a peptide sequence as follows: (pyro)Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH.sub.2. The conventional abbreviations for the various common amino acids are used as generally accepted in the peptide art as recommended by the IUPAC-IUB Commission on Biological Nomenclature. The N-terminal amino acid is written on the left and the C-terminal amino acid on the right. The most significant chemical modification of the basic natural LH-RH molecule leading to increased activity has been obtained by changing the 6-position amino acid residue from glycine to a D-amino acid. Particularly active analogues are those where the Gly residue in the 6-position is replaced by D-Phe, D-Trp, D-Leu, D-Ala or D-Ser(t-Bu).
In addition, further increases in activity have been obtained by replacing the Gly-NH.sub.2 terminus by a Pro-NHR terminus, where R is, for example, lower alkyl (preferably ethyl), cycloalkyl, fluoroalkyl or ##STR1## ("Aza-Gly"-NHR.sup.1) where R.sup.1 is hydrogen or lower alkyl. Coupling of this modification with the aforementioned modification in the 6-position leads to highly active compounds.
Especially active LH-RH super agonists heretofore described are:
[D-Phe.sup.6 ]LHRH, [D-Trp.sup.6 ]LHRH, [D-Leu.sup.6 ]LHRH, [D-Ala.sup.6 ]LHRH, desGly.sup.10 -[D-Phe.sup.6, ProNHEt.sup.9 ]LHRH, desGly.sup.10 -[D-Trp.sup.6, ProNHEt.sup.9 ]LHRH, desGly.sup.10 -[D-Ala.sup.6, ProNHEt.sup.9 ]LHRH, desGly.sup.10 -[D-Leu.sup.6, ProNHEt.sup.9 ]LHRH, desGly.sup.10 -[D-Ser(t-Bu).sup.6, ProNHEt.sup.9 ]LHRH and desGly.sup.10 -[D-Ser(t-Bu).sup.6, Aza-Gly-NH.sub.2.sup.10 ]LHRH. The nomenclature is that generally accepted in the LH-RH art, wherein the nature and position of modifications to the natural LH-RH are shown before and within the brackets.
While these compounds are highly active and exhibit a relatively long biological halflife (e.g. 8-10 hours) in comparison to the natural LH-RH (1-2 hours), it would be desirable to have available pharmaceutical compositions for depot injectable use that could provide, in a single administration, release of effective amounts of the LH-RH analogue over periods of from 1 week to as much as 1 year.
The use of complexing agents such as tannic acid, and gelling agents such as aluminum monostearate to control drug solubility and the rate of drug transfer, respectively, is generally known. See, for example, "Sustained and Controlled Release Drug Delivery Systems", J. R. Robinson, Ed, Marcel Dekker, Inc. New York, 1978, pp. 178 and 189.